Bis(dioxopieperazines) are of considerable import owing to their antimetastatic properties and their actions ameliorating anthracycline-induced toxicity in animals as reported by Herman et al., 19 Adv. in Pharmacol. and Chemother. 249(1982). Cyclopropyl-bis(dioxopiperazines), as reported in Witiak et al., 21 J. Med. Chem., 1194(1978) and Zwilling et al, 44 Brit. J. Cancer 578 (1981), and related tetraazaperhydrophenanthrenes as reported in Witiak et al, 24 J. Med. Chem. 1329 (1981) have been employed to assess stereoselective antimetastatic properties. Although a "cisoid" relationship of dioxopiperazine rings seems to be important for antimetastatic activity, pretreatment of B16F10 cells for 24 hours with trans-anti-trans-1, but not cis-syn-trans-2, significantly inhibited metastases following their injection into the tail vein of C57B1/6J mice, as reported by Witiak et al., 24 J. Med. Chem., 1329 (1981).
A morpholinomethyl analogue of ICRF-154, an open chain compound related to compounds 1 and 2 shown below, namely bis-(4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-ethane) was reported by Ren et al. Kexue Tongbao, 1980:25, 189, to be active, by both the oral and ip routes, against various experimental tumors. Results of the clinical investigations in China indicated that this compound may be useful in the treatment of malignant lymphomas, uveitis, sympathetic ophthalmitis and psoriasis (Ren et al., supra). It is therefore apparent that the correlation between the structure of morpholinomethyl-N groups and their behavior in vivo is not well-understood and there is a continuing need for the development of pharmacologically and clinically effective antitumor, anti-metastatic bis(morpholinomethyl) derivatives of tricyclic bis(dioxopiperazines).